This proposal describes a five-year plan to thoroughly investigate a novel pathway that regulates thermogenic beige fat cells through the alpha 2 subunit of the nicotinic acetylcholine receptor, CHRNA2. The research strategy includes a significant amount of compelling preliminary data, and rigorous experimental approaches to test our hypotheses and reveal the therapeutic potential of activating beige fat to treat obesity. Obesity has emerged as a major threat to public health, emphasizing the importance of developing effective therapeutic interventions. Essentially a disorder of energy balance, obesity occurs when energy intake exceeds expenditure. Our previous work led to the isolation of a new type of thermogenic adipocyte, the beige adipocyte, which regulates both energy-storage similarly to white adipocytes and energy-expenditure like brown adipocytes. Our data and numerous follow-up studies have identified beige fat in human adults, raising the prospect of inducing thermogenic activity in fat to protect against obesity in humans. Whereas the regulation of white and brown adipocytes has been studied for decades and is relatively well understood, little is known with regard to the molecular mechanisms and signaling networks that regulate beige fat. As the first step towards exploring therapeutic potential of beige fat, we investigated the unique expression pattern of activated beige fat. These studies revealed that CHRNA2 is upregulated by many thermogenic stimulants in beige fat cells. Immunohistochemical analysis and calcium uptake in response to agonist revealed that CHRNA2 functions in a beige-fat-specific manner. Moreover, CHRNA2 agonists appear to regulate the thermogenic program of beige adipocytes, likely through interactions with the adrenergic signaling pathway. Consequently, CHRNA2 KO mice have reduced thermogenic gene expression in beige but not brown fat upon cold exposure. We hypothesize that CHRNA2 plays a key role in mediating a novel pathway that integrates various thermogenic signals specifically in beige adipocytes, and significantly influences systemic metabolism through activating beige fat function. We propose to investigate how the expression of this channel is increased, how CHRNA2 signaling interacts with adrenergic signaling to control the thermogenic response through the cAMP/PKA pathway, and finally what are the functional consequences of this pathway in regulating whole body metabolism. Proposed studies here will shed light on the basic mechanisms underlying beige- specific regulation through CHRNA2-mediated signaling and reveal the impact on systemic metabolic homeostasis through beige fat activation by CHRNA2 and may suggest new approaches for the prevention and treatment of obesity and its associated medical conditions, including diabetes.